Bis-cephalosporins

ABSTRACT

DERIVATIVES OF DIFUNCTIONAL COMPOUNDS SUCH AS DICARBOXYLIC ACID, DIISOCYANATES OR DIISOTHIOCYANATES WHEREIN EACH FUNCTIONAL GROUP IS REACTED WITH 7-AMINOCEPHALOSPORANIC ACID OR 7-AMINODESACETOXYCEPHALOSPORANIC ACID POSSESS ANTIBACTERIAL ACTIVITY.

United States Patent 3,825,536 BIS-CEPHALOSPORINS Donald J. Perrella, Princeton Junction, and Joseph E. Dolfini, Princeton, N.J., assignors to E. R. Squibb & Sons,.Inc., Princeton, NJ. N0 Drawing. Filed Sept. 22, 1972, Ser. No. 291,442

l 1 Int. Cl. C07d 99/24 U.S. Cl.'260---243C. l 11 Claims ABSTRACT OF THE DISCLOSURE Derivatives .of difunctional compounds such as dicarboxylic acid, diisocyanates or diisothiocyanates wherein each functional group' is reacted with 7-aminocephalosporanic acid or 7-aminodesacetoxycephalosporanic acid possess antibacterial activity.

SUMMARY OF THE INVENTION The antibacterial agents of the present invention comprise derivatives of dior higher polyfunctional compounds such as dior higher polycarboxylic acids or dior higher polyisocyanates or isothiocyanates wherein at least two'functional. groups are reacted with 7-aminocephalosporanic acid (7-ACA) or 7-aminodesacetoxycephalosporanic acid (7-ADCA).

DETAILED DESCRIPTION The dior higher polyfunctional starting compounds of the present invention comprise dior higher polycarboxylic acids or dior higher polyisocyanates or dior higher polyisothiocyanates. At least two functional groups of the starting compound are reacted with the same or dilferent antibacterial moiety. The antibacterial moieties of the present invention comprise 7-ACA or 7-ADCA or derivatives thereof. By way of illustration, each carboxyl groupof adicarboxylic acid may be reacted with the amino group ,of 7-ACA or 7-ADCA, or one carboxyl group reactedfwith the amino group of 7-ACA and one carboxyl group reactedwithfthe amino group or 7-ADCA.

In the case of a diisocyanate, each isocyanate group may be reacted with the amino group of 7-ACA or 7-ADCA or one isocyanate group may be reacted with the amino group of'7-ACA andone isocyanate group reacted with the amino group of 7-ADCA.

Various types of polyfunctional compounds may be used inthe present invention. The polyfunctional compound may be aliphatic, alicyclic, aromatic or heterocyclic. By way of illustration, some examples for each group follow.

I. Polybasic Acids l. Aliphatic acids-oxalic, fumaric, malonic, maleic,

succinic, tartaric, glutaric, adipic, pimelic, suberic, azelaic, sebacic, etc.

2. ,;Alicyclic. acids tetrahydrophthalic, hexahydroph II. Diisocyanates l. Aliphatic isocyanatesethylene diisocyanate, propylene-1,2-diisocyanate, butylene 1,3 diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, 1,2,4-butane triisocyanate, etc., and the corresponding isothiocyanates;

2. Alicyclic isocyanates-1,2 diisocyanocyclohexane, 1,3 diisocyanocyclohexane, 1,4 diisocyanocyclohexane, cyclopentyl 1,3 diisocyanate, etc., and the corresponding isothiocyanates;

3. Heterocyclic isocyanatespyridine-2,6-diisocyanate, furan 2,5 diisocyanate, thiophene-2,4-diisocyanate, thiophene 2,5 diisocyanate, pyrimidine 4,6 diisocyanate, pyrimidine 4,5,6 triisocyanate, etc., and the corresponding isothiocyanates.

The compounds of the present invention include the free acids as well as physiologically acceptable metal salts, esters, or salts of physiologically acceptable organic bases. Examples of suitable metal salts include the alkili metal and alkaline earth metal salts, e.g., the Na, K, Mg and Ca. The ammonium ion may be included among the alkali metals. Examples of suitable esters include radicals derived from alcohols of up to 7 carbon atoms, e.g., methyl, propyl, t-butyl, trichloroethyl, pivaloyloxymethyl, benzyl, p-nitrophenyl, trimethyl silyl, trimethyl stannyl, methoxymethyl, and the like. Examples of suitable bases include substituted ammonium salts, e.g., salts of nontoxic amines such as trialkylamines, including triethylamine, procaine, dibenzylamine, N-benzyl 18 phenethylamine, N,N dibenzylethylenediamine, N-(lower)-alkylpiperidine, e.g., N-ethylpiperidine and other amines which have been used to form salts with benzylpenicillin and the like. The foregoing metal salts or organic bases and esters are prepared according to known techniques.

The compounds of this invention form salts which are also part of the invention. Basic salts form with the carboxyl group of the 7-ACA or 7-ADCA moiety. It is frequently convenient to isolate and purify the product by forming a soluble or insoluble salt, as desired, then regenerating the free compound, by neutralization for example.

The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella schottmuelleri, Presudomonas aerugz'nosa, Proteus vulgaris, Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to penicillin G and other penicillins and cephalosporins. For example, a compound of the invention or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 0.1 to mg./kg. daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin. Up to about 600 mg. of a compound of the invention or a salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice. In cleaning or disinfecting compositions, e.g., in barns or dairy equipment, a concentration of about 0.01 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying may be used.

The compounds of the present invention may be readily prepared by reacting either 7-ACA or 7-ADCA, the carboxyl group of which is protected, with an acyl dihalide, or an isocyanate or an isothiocyanate. The reaction takes place in an inert solvent such as, for'example, chloroform,

,benzene, toluene, ethylene chloride, methylene chloride,.

dioxane, nitromethane, acetonitrile, dimethylformamide or diethyl ether, or mixtures of the foregoing solvents. The carboxyl group of either the 7ACA or 7ADCA moiety may be protected by any convenient ester group which will not interfere with reaction between the amino group of either the 7-ACA or 7ADCA moiety and either the acyl halide or isocyanate compound. The reaction takes place at temperatures in the range of from about 30 C. to about 20 C.

While examples of specific polycarboxylic acids and polyisocyanates or polyisothiocyanates have been given previously, it is to be understood that any polycarboxylic acid, polyisocyanate or polyisothiocyanate may be employed according to the present invention provided no substituents are present which would interfere with the reaction with the antibacterial moiety. With the foregoing understanding, the following paragraphs describe preferred compounds.

The aliphatic polycarboxylic acids, examples of which have been given previously, comprise polyalkanoic or polyalkenoic acids of from 2 to about 12 carbon atoms (including those in the carboxyl groups). The acid may be substituted, e.g., by a halogen.

The alicyclic polycarboxylic acids, examples of which have been given previously, comprise cycloalkyl or cycloalkenyl compounds of 5 or 6 carbon atoms in the ring, and a total of from 7 to about carbon atoms (including those in the carboxyl groups), or a bicyclic ring system having a total of about 9 carbon atoms (including those in the carboxyl groups).

The aliphatic polyisocyanates or polyisothiocyanates, examples of which have been given previously, comprise polyisocyanates or polyisothiocyanates of from 2 to about 10 carbon atoms (including those in the isocyanate or isothiocyanate groups).

The alicyclic polyisocyanates or polyisothiocyanates, examples of which have been given previously, comprise cycloalkyl compounds of 5 or 6 carbon atoms in the ring which carbons may be substituted by a methyl group or by a halogen, and which compounds have a total of from 7 to about 10 carbon atoms (including those in the isocyanate or isothiocyanate groups).

The following examples illustrate the present invention without, however, limiting the same thereto. All temperatures are expressed in degrees Celsius.

EXAMPLE 1 N,N'-Oxalylbis[7-Aminocephalosporanic Acid] A solution of 7-aminocephalosporanic acid (2 mmole) and triethylamine (4 mmole) in mg. of pure chloroform is cooled to -10 C. Trimethylsilyl chloride (4 mmole) is then added over a ten-minute interval. The resulting mixture is stirred for about thirty minutes more. Triethylamine (2 mmoles) is again added followed by a solution of oxalyl chloride (1 mmole) in 10 ml. of pure chloroform added over a ten-minute interval, the temperature being maintained at l0 C. After an additional one hour of stirring at this temperature, the reaction mixture is poured into cold water and the pH adjusted to about 3.5. The chloroform layer containing the product is separated. This organic layer is then layered with water and the pH of the aqueous layer adjusted to pH 7.5 with dilute sodium hydroxide with vigorous shaking of the mixture. The chloroform layer is drawn off and the aqueous solution of the product is layered with ethyl acetate. The pH of the aqueous solution is lowered to 3.5; the ethyl acetate layer is washed with water and saturated aqueous sodium chloride. After drying and evaporating the ethyl acetate layer, the title compound is obtained.

EXAMPLE 2 N,N-Succinoylbis[7-Aminocephalosporanic Acid] Following the procedure of Example 1 but substituting 1 mmole of succinoyl chloride in place of oxalyl chloride, the title compound is obtained.

4 EXAMPLE 3 Following the procedure of Example 1 but substituting 1 mmole of adipoyl chloride in place of oxalyl chloride, the title compound is obtained.

EXAMPLE 4 N,N'-Sebacoylbis[7-Aminocephalosporanic Acid] Following the procedure of Example 1 but substituting 1 mmole of sebacoyl chloride in place of oxalyl chloing 1 mmole of terphaloyl chloride in place of oxalyl chloride, the title compound is obtained.

EXAMPLE 6 N,N'-Isophthaloylbis[7-Aminocephalosporanic Acid] Following the procedure of Example 1 but substituting 1 mmole of isophthaloyl chloride in place of oxalyl chloride, the title compound is obtained.

EXAMPLE 7 N,N-Phthaloylbis [7-Aminocephalosporanic Acid] Following the procedure of Example 1 but substitut-,

ing 1 mmole of phthaloyl chloride in place of oxalyl chloride, the title compound is obtained.

EXAMPLE 8 N,N'-Tetrahydrophthaloylbis[7-Aminocephalosporanic Acid] Following the procedure of Example 1 but substituting 1 mmole of tetrahydrophthaloyl chloride in place of oxalyl chloride, the title compound is obtained.

EXAMPLE 9 N,N'-Endomethylenetetrahydrophthaloylbis[7- Aminocephalosporanic Acid] Following the procedure of Example 1 but substituting 1 mmole of endomethylenetetrahydrophthaloyl chloride in place of oxalyl chloride, the title compound is obtained.

EXAMPLE 10 N,N-Camphoroylbis[7-Aminocephalosporanic Acid] Following the procedure of Example 1 but substituting 1 mmole of camphoroyl chloride in place of oxalyl chloride, the title compound is obtained.

EXAMPLE 11 Ethylenediamine-bis-N,N-(7-Carbonylaminocephalosporanic Acid) Folowing the procedure of Example 1 but substituting 1 mmole of ethylenediisocyanate for oxalyl chloride,

the title compound is obtained.

EXAMPLE 12 1,4-Cyclohexyldiamine-bis-N,N- (7-Carbonylaminocephalosporanic Acid) Following the procedure of Example 1 but substitut-.

ing 1 mmole of 1,4-cyclohexyldiisocyanate for oxaly chloride, the title compound is obtained.

EXAMPLES 13-27 Following the procedure of Example 1 but substitut-' ing 7-aminodesacetoxycephalosporanic acid for 7-aminocephalosporanic acid inJ-Examples 1-15, the following compoundsare obtained: v

Example com ound 13 N,N'-oxalylbis[7-aminodesacetoxycephalosporanic acid]. 14- N,N-succinoylbisl7-aminodesacetoxycephalosporanic acid]. 15- N,N-adlpoylbis[7-aminodesacetoxyeephalosporanic acid].

16. N,N-sebac0ylbis[7-aminodesacetoxycephalosporanic acid].

17 N,N-terphthaloylbis[7-aminodesacetoxycephalosporanic 18 N,I {-isophthaloylbis[7-aminodesacetoxycephalosporanic 19 N,N-phthaloylbis[7-aminodesacetoxycephalosporanic acid].

20 N,N-tetrahydrophth'aloylbis[7-aminodesacetoxycephalosporauie acid].

21- N,N-endomethylenetetrahydrophthaloylbisI7-amin0- desacetoxycephalosporanic acid N,N-camphoroylbis[7-aminodesacetoxycephalosporamc acid]. 7

23 N,N'-(3,4-pyridinedicarbonyl)-bis-[7-arninodesacetoxycephalosporanic aci 24 N,bl'-qu.inolinoylbis[7aminodesacetoxvycephalosporanlc aci 25 ethy1enediamine .bis-N,N'-(7-carbonylaminodesacetoxyeephalosporamc acid).

26 lA-phenylenediamine-bis-N,N'-(7-carbonylamlnodesacetoxycephalosporanic acid).

27- 1,Myclohexyldiaminabis-N,N-(7carbony1aminodesacetoxycephalosporanie acid).

EXAMPLES 28-3 6 Following the procedure of Example 1 but substituting for oxalyl chloride 1 mmole of the compound in Column I, there is obtained a compound of the following formula wherein R is the radical indicated in Column H and Y is as indicated in Column IH.

Succinoyl N-(7-Aminodesacetoxycephalosporanic Acid)- N-(7-Aminocephalosporanic Acid) A solution of one mmole of 7 -ADCA and 2 mmoles of triethylamine in 30 ml. of pure chloroform at ambient temperature is treated with one mmole of pure trimethylsilyl chloride. After stirring for one hour, one mmole of succinic anhydride is added with one mmole of additional triethylamine. The mixture is stirred fprabout one hour. After chilling to 0 C., oneummole of "ethyl chloroformate is then added. After 15 minutes asolution of one mmole of 7-ACA and 2 mmoles of triethylamine in chloroform is added. The coolant is then removed and the reaction allowed to proceed for one hour. The reaction is then diluted with an equal volume of chloroform and extracted with several portions of cold 0.1 N aqueous hydrochloric acid, then washed with water. The organic solution is extracted with several volumes of pH 7.5 phosphate buffer. The aqueous extract is then acidified to about pH 3.5 and extracted with several volumes of ethyl acetate. The ethyl acetate extract is washed with water, then dried (Na SO and evaporated at reduced pressure to deposit the title compound.

EXAMPLES 38-39 Following the procedure of Example 37 but substituting for succinic anhydride one mole of the compound listed in Column I, the product obtained is indicated in Column H.

Example I II 38 Terephthalic acid.-." Terephthaloyl N-(7-aminodesacetoxycephalosporanic acid)-N'- (7-aminoc'ephalosporanic acid). 39 Hexahydrophthallc Hexahydrq'phthaloyl N-(7- acid. aminodesacetoxycephalosporanic acid)-N'-(7-aminocephalosporanic acid).

What is claimed is: 1. A compound of the formula wherein R is aliphatic group of from 2 to 10 carbon atoms, monocyclic alicyclic group of 5 or 6 carbon atoms in the ring; bicyclic alicyclic group of 8 to 10 carbon atoms; X is each Q is the same.

2. A compound according to claim 1 wherein X is Q is CH and n is 2.

3. A compound according to claim 1 wherein X is Q is CH OCOCH and n is 2.

4. A compound according to claim 1 wherein X is H o I l- 3-, Q is CH and n is 2.

5. A compound according to claim 1 wherein X is 6 .'A compound accordmg'to claim 1' wherein Q is cH' and n is 2.

7. A compound according to claim 1 wherein X is JHL,

Q is --CH OCOCH and n is 2.

8. A compound of claim 1 wherein R is a divalent alkyl or alkylene group of up to 6 carbon atoms.

9. A compound according to claim 1 wherein R is alicyclic group of 5 to or 6 carbon atoms.

8 i? 10.-"A compound according to claim 1 wherein n is 2,

one Q is CH;; and the other Q is--CHOCOCH l-L A compound according toclaim Lhaving the name N '-.9 y b s- 5 I a 7' References Cited f UNITEDSTATES PATENTS 3,264,291 8/1966 Sch enker et a1. 1--- 260--243 0 3,196,151 7/1965 Hoover et a1 260-243 0 U.S. (51. xx 15 424246 $553 3? STATES PATENT OFFICE v V CERTIFICATE OF CORRECTIQNY' Patent No. 3,825,536 Da ed Jul 23, 1974 lnvent fl Donald J.- Perrella et al.

It: is certified that error appears- 1n the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, delete lines 11-15.

Column 2, line 19, "alkili" should read -alkali-.

Column 2, line 45, "Presudomonas" should read Pseudomonas-. Column 4, line 2, "Adipolybis" should read Adip0ylbis Column 4, line 17, ""terphaloyl" should read -terph thaloyl--. Column 5-, examples 28-36, in the formula /S should read E s, H C CH Column 6, 7 line 53., after "and'? insert -when-. Column 7-, line 11, "CH OCOCH" should read CH OCOCH' Si ned and sealed this 8th daylofi October 1974.- v

( SEAL) Attest:

MCCOY M. GIBSON JR. s 4 C. MARSHALL DANN Attesting Officerv. Commissioner of' Patents 

